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A new type of molecular arrangement for dipeptides is observed in the crystal structure of L-phenyl­alanyl-L-alanine dihydrate, C12H16N2O3·2H2O. Two L-Phe and two L-Ala side chains aggregate into large hydro­phobic columns within a three-dimensional hydrogen-bond network.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S010827010100155X/da1163sup1.cif
Contains datablocks I, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S010827010100155X/da1163Isup2.hkl
Contains datablock I

CCDC reference: 164651

Comment top

Dipeptides with two hydrophobic residues (L-Ala, L-Val, L-Leu, L-Ile, L-Met and L-Phe) have a high propensity to form cocrystals with organic solvent molecules. The structures of these solvates are invariably divided into distinct hydrophobic and hydrophilic layers (Görbitz, 1999, and references therein). When organic solvents are not used for crystallization purposes, a much more heterogeneous group of crystal-packing arrangements results. Structures with two-dimensional layers of peptide main chains have been observed [L-Met-L-Met (Stenkamp & Jensen, 1975), L-Leu-L-Ala tetrahydrate (Görbitz, 1997) and L-Phe-L-Val (Görbitz, 2000)], as well as honeycomb patterns with hexagonally symmetric hydrophobic columns along a ~10 Å long c axis [L-Val-L-Ala (Görbitz & Gundersen, 1996a), L-Leu-L-Val 0.75-hydrate (Görbitz & Gundersen, 1996b), and L-Val-L-Val, L-Ala-L-Val and L-Ile-L-Ala (Görbitz, 2001)]. The L-Leu/Phe-L-Leu/Phe series, on the other hand, form structures with hydrophilic columns and one-dimensional hydrogen-bond patterns (Görbitz, 2001). L-Ala-L-Ala (Fletterick et al., 1971) has a unique combination of hydrophobic columns and tetragonal symmetry.

All bond lengths and angles for L-Phe-L-Ala dihydrate, (I), shown in Fig. 1, are normal. The peptide main chain is fairly extended and the L-Phe side chain is in the common gauche- conformation. The aromatic ring is perfectly planar; the r.m.s. distance of ring C atoms from the ring plane is just 0.0021 Å.

The crystal structure and unit cell are depicted in Fig. 2. The molecular arrangment is new for dipeptides, but it is reminiscent of the L-Ala-L-Ala structure (Fletterick et al., 1971) in that groups of four side chains constitute hydrophobic columns within a rectangular hydrogen-bond pattern. The types of hydrogen bonds are, however, completely different in the two structures. All three amino H atoms in L-Ala-L-Ala are donated to C-terminal carboxylate groups, while only one such interaction is present in the title structure, in which it generates a pleated head-to-tail chain parallel to the b axis. There are no other direct contacts between the peptide molecules. Hydrogen-bond parameters are given in Table 2. It is interesting to note that O50 is involved in four short hydrogen bonds [d(O···H) < 2.0 Å] as a link between charged amino and carboxylate groups. O40, on the other hand, participates in just one short interaction (as a donor to a carboxylate group). The shortest interaction with O40 as acceptor has a peptide bond N—H as donor and d(O···H) = 2.186 (13) Å. Consequently, thermal motion is significantly larger for O40 (Ueq = 0.034 Å2) than for the more fixed O50 (Ueq = 0.024 Å2), as is also readily observed in Fig. 1.

Due to the comparatively long a axis (most dipeptides have an axis in the 5–6 Å range) the `herring-bone' pattern generated by the aromatic rings is quite stretched out and unusual in that neighboring rings related by a twofold screw axis make an angle of only 35.9°. The centroid–centroid separation is 5.15 Å and the shortest H···C distance for Car—H···Car contacts is 3.15 Å. There are no contacts between rings related by translation along the a axis.

Related literature top

For related literature, see: Flack (1983); Fletterick et al. (1971); Görbitz (1997, 1999, 2001); Görbitz & Gundersen (1996a, 1996b); Stenkamp & Jensen (1975).

Experimental top

L-Phe-L-Ala was obtained from Sigma and was used as received. Needle-shaped crystals were grown by slow evaporation of an aqueous solution of the peptide at 276 K.

Refinement top

Positional parameters were refined for H atoms involved in hydrogen bonds. Other H atoms were placed geometrically and refined with constraints to keep all C—H distances and C—C—H angles on any one C atom the same. Free rotation of the L-Ala methyl group was permitted. Uiso values were 1.2Ueq of the carrier atom or 1.5Ueq for water molecules. For the amino and methyl groups, two free variables were refined for Uiso. Intensities were measured for 2863 Friedel pairs. The absolute structure was known for the purchased material. The Flack x parameter [0.1 (5); Flack, 1983] does not allow this to be determined from the refinement (Flack & Bernardinelli, 2000).

Computing details top

Data collection: SMART (Bruker, 1998); cell refinement: SAINT (Bruker, 1998); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 1997); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Figures top
[Figure 1] Fig. 1. The structure of L-Phe-L-Ala dihydrate with the atomic numbering indicated. Displacement ellipsoids are shown at the 50% probability level and H atoms are shown as spheres of arbitrary size.
[Figure 2] Fig. 2. The unit cell and molecular packing viewed along the a axis. Hydrogen bonds are shown as dashed lines.
L-Phenylalanyl-L-alanine dihydrate top
Crystal data top
C12H16N2O3·2H2ODx = 1.211 Mg m3
Mr = 272.30Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121Cell parameters from 6235 reflections
a = 7.6541 (2) Åθ = 2.2–35.0°
b = 11.0918 (3) ŵ = 0.09 mm1
c = 17.5990 (5) ÅT = 150 K
V = 1494.12 (7) Å3Needle, colourless
Z = 40.70 × 0.26 × 0.18 mm
F(000) = 584
Data collection top
Siemens SMART CCD
diffractometer
6554 independent reflections
Radiation source: fine-focus sealed tube5553 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.021
Detector resolution: 8.3 pixels mm-1θmax = 35.0°, θmin = 2.2°
Sets of exposures each taken over 0.6° ω rotation scansh = 1211
Absorption correction: empirical (using intensity measurements)
(SADABS; Sheldrick, 1996)
k = 1717
Tmin = 0.936, Tmax = 0.983l = 2628
19962 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.035H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.090 w = 1/[σ2(Fo2) + (0.0588P)2]
where P = (Fo2 + 2Fc2)/3
S = 1.02(Δ/σ)max = 0.004
6554 reflectionsΔρmax = 0.30 e Å3
210 parametersΔρmin = 0.16 e Å3
0 restraintsAbsolute structure: Flack (1983)
Primary atom site location: structure-invariant direct methodsAbsolute structure parameter: 0.1 (5)
Crystal data top
C12H16N2O3·2H2OV = 1494.12 (7) Å3
Mr = 272.30Z = 4
Orthorhombic, P212121Mo Kα radiation
a = 7.6541 (2) ŵ = 0.09 mm1
b = 11.0918 (3) ÅT = 150 K
c = 17.5990 (5) Å0.70 × 0.26 × 0.18 mm
Data collection top
Siemens SMART CCD
diffractometer
6554 independent reflections
Absorption correction: empirical (using intensity measurements)
(SADABS; Sheldrick, 1996)
5553 reflections with I > 2σ(I)
Tmin = 0.936, Tmax = 0.983Rint = 0.021
19962 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.035H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.090Δρmax = 0.30 e Å3
S = 1.02Δρmin = 0.16 e Å3
6554 reflectionsAbsolute structure: Flack (1983)
210 parametersAbsolute structure parameter: 0.1 (5)
0 restraints
Special details top

Refinement. Refinement of F2 against ALL reflections.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.67853 (8)0.33830 (7)0.88345 (4)0.03518 (15)
O20.67409 (8)0.63984 (6)0.68676 (4)0.02984 (13)
O30.95867 (8)0.60098 (7)0.67099 (4)0.03378 (15)
N10.33785 (8)0.31821 (6)0.91846 (4)0.01974 (11)
H10.2280 (17)0.3245 (12)0.9343 (7)0.0300 (16)*
H20.3391 (17)0.2540 (12)0.8859 (7)0.0300 (16)*
H30.4086 (17)0.3047 (11)0.9591 (7)0.0300 (16)*
N20.62386 (8)0.46885 (6)0.78635 (4)0.02280 (12)
H40.5484 (17)0.5107 (12)0.7658 (7)0.027*
C10.39416 (9)0.42723 (7)0.87651 (4)0.01994 (12)
H110.3155 (16)0.4410 (11)0.8320 (7)0.024*
C20.39292 (11)0.53875 (7)0.92869 (5)0.02682 (15)
H210.4676 (7)0.52529 (15)0.9693 (4)0.032*
H220.4349 (4)0.6046 (6)0.9018 (3)0.032*
C30.21290 (11)0.56794 (7)0.95885 (5)0.02452 (14)
C40.17276 (14)0.54959 (9)1.03513 (5)0.03576 (19)
H410.2617 (14)0.5171 (5)1.0697 (6)0.043*
C50.00623 (17)0.57719 (12)1.06264 (6)0.0457 (3)
H510.0230 (5)0.5628 (3)1.1185 (9)0.055*
C60.11939 (15)0.62408 (10)1.01423 (7)0.0427 (2)
H610.238 (2)0.6444 (3)1.0342 (3)0.051*
C70.08040 (13)0.64288 (9)0.93803 (6)0.03666 (19)
H710.1648 (13)0.6744 (5)0.9054 (5)0.044*
C80.08534 (12)0.61454 (8)0.91054 (5)0.02916 (16)
H810.1126 (4)0.62754 (19)0.8565 (7)0.035*
C90.58011 (9)0.40641 (7)0.84789 (4)0.02174 (13)
C100.80151 (9)0.47668 (7)0.75666 (4)0.02111 (13)
H1010.8809 (9)0.4937 (2)0.7992 (5)0.025*
C110.86078 (12)0.35977 (8)0.71843 (5)0.03125 (17)
H1110.8599 (12)0.2979 (6)0.7535 (3)0.048 (2)*
H1120.9725 (11)0.3695 (3)0.6996 (5)0.048 (2)*
H1130.7857 (10)0.3413 (5)0.6790 (5)0.048 (2)*
C120.81124 (10)0.58229 (7)0.70031 (4)0.02198 (13)
O400.69949 (9)0.07586 (7)0.78020 (4)0.03434 (14)
H4010.806 (2)0.0793 (15)0.7920 (9)0.052*
H4020.646 (2)0.1299 (15)0.8030 (9)0.052*
O500.98801 (7)0.25903 (6)0.94197 (3)0.02408 (11)
H5011.0067 (18)0.2136 (14)0.9051 (8)0.036*
H5020.904 (2)0.2998 (13)0.9259 (7)0.036*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0200 (2)0.0481 (4)0.0375 (3)0.0094 (3)0.0039 (2)0.0214 (3)
O20.0242 (3)0.0285 (3)0.0368 (3)0.0046 (2)0.0035 (2)0.0116 (2)
O30.0202 (3)0.0391 (3)0.0421 (4)0.0019 (2)0.0023 (2)0.0167 (3)
N10.0157 (2)0.0211 (3)0.0224 (3)0.0009 (2)0.0010 (2)0.0006 (2)
N20.0161 (2)0.0270 (3)0.0252 (3)0.0042 (2)0.0023 (2)0.0070 (2)
C10.0156 (3)0.0217 (3)0.0226 (3)0.0016 (2)0.0015 (2)0.0012 (2)
C20.0226 (3)0.0224 (3)0.0355 (4)0.0024 (3)0.0047 (3)0.0040 (3)
C30.0261 (3)0.0175 (3)0.0300 (3)0.0005 (3)0.0057 (3)0.0025 (2)
C40.0384 (5)0.0385 (5)0.0303 (4)0.0088 (4)0.0052 (3)0.0041 (3)
C50.0475 (6)0.0551 (6)0.0344 (5)0.0103 (5)0.0172 (4)0.0038 (5)
C60.0349 (5)0.0467 (6)0.0466 (5)0.0103 (4)0.0137 (4)0.0080 (4)
C70.0309 (4)0.0382 (4)0.0409 (5)0.0106 (4)0.0010 (4)0.0048 (4)
C80.0301 (4)0.0273 (4)0.0301 (4)0.0035 (3)0.0038 (3)0.0007 (3)
C90.0160 (3)0.0251 (3)0.0242 (3)0.0021 (2)0.0016 (2)0.0029 (3)
C100.0160 (3)0.0243 (3)0.0231 (3)0.0018 (2)0.0016 (2)0.0040 (2)
C110.0337 (4)0.0258 (4)0.0343 (4)0.0077 (3)0.0099 (3)0.0050 (3)
C120.0203 (3)0.0223 (3)0.0234 (3)0.0017 (2)0.0008 (2)0.0028 (2)
O400.0221 (3)0.0413 (4)0.0397 (3)0.0053 (3)0.0024 (2)0.0116 (3)
O500.0175 (2)0.0300 (3)0.0247 (2)0.0042 (2)0.00093 (19)0.0010 (2)
Geometric parameters (Å, º) top
O1—C91.2369 (9)C4—H410.9818
O2—C121.2515 (10)C5—C61.3859 (18)
O3—C121.2580 (10)C5—H511.0211
N1—C11.4809 (10)C6—C71.3896 (16)
N1—H10.888 (13)C6—H611.0007
N1—H20.914 (13)C7—C81.3936 (13)
N1—H30.910 (13)C7—H710.9322
N2—C91.3284 (9)C8—H810.9838
N2—C101.4593 (9)C10—C111.5297 (11)
N2—H40.825 (13)C10—C121.5365 (10)
C1—C91.5273 (9)C10—H1010.9829
C1—C21.5407 (11)C11—H1110.9233
C1—H111.000 (12)C11—H1120.9233
C2—C31.5116 (11)C11—H1130.9233
C2—H210.9272O40—H4010.839 (19)
C2—H220.9272O40—H4020.829 (17)
C3—C41.3921 (12)O50—H5010.834 (15)
C3—C81.3940 (12)O50—H5020.834 (15)
C4—C51.3974 (15)
C1—N1—H1111.6 (8)C5—C6—C7120.04 (9)
C1—N1—H2108.7 (8)C5—C6—H61120.0
H1—N1—H2105.6 (12)C7—C6—H61120.0
C1—N1—H3110.7 (8)C6—C7—C8119.78 (10)
H1—N1—H3109.2 (11)C6—C7—H71120.1
H2—N1—H3111.1 (11)C8—C7—H71120.1
C9—N2—C10123.91 (6)C7—C8—C3120.63 (8)
C9—N2—H4118.3 (9)C7—C8—H81119.7
C10—N2—H4117.5 (9)C3—C8—H81119.7
N1—C1—C9108.19 (6)O1—C9—N2125.26 (7)
N1—C1—C2110.89 (6)O1—C9—C1119.54 (7)
C9—C1—C2108.89 (6)N2—C9—C1115.15 (6)
N1—C1—H11109.9 (7)N2—C10—C11112.54 (7)
C9—C1—H11109.0 (7)N2—C10—C12108.76 (6)
C2—C1—H11109.9 (7)C11—C10—C12110.37 (6)
C3—C2—C1112.76 (6)N2—C10—H101108.4
C3—C2—H21109.0C11—C10—H101108.4
C1—C2—H21109.0C12—C10—H101108.4
C3—C2—H22109.0C10—C11—H111109.5
C1—C2—H22109.0C10—C11—H112109.5
H21—C2—H22107.8H111—C11—H112109.5
C4—C3—C8119.19 (8)C10—C11—H113109.5
C4—C3—C2120.56 (8)H111—C11—H113109.5
C8—C3—C2120.24 (7)H112—C11—H113109.5
C3—C4—C5120.22 (9)O2—C12—O3126.17 (7)
C3—C4—H41119.9O2—C12—C10118.11 (7)
C5—C4—H41119.9O3—C12—C10115.71 (7)
C6—C5—C4120.14 (9)H401—O40—H402108.8 (16)
C6—C5—H51119.9H501—O50—H502101.2 (13)
C4—C5—H51119.9
N1—C1—C9—N2153.99 (7)C4—C5—C6—C70.50 (19)
C1—C9—N2—C10170.21 (7)C5—C6—C7—C80.06 (18)
C9—N2—C10—C12164.26 (7)C6—C7—C8—C30.29 (15)
N2—C10—C12—O22.32 (10)C4—C3—C8—C70.19 (14)
N2—C10—C12—O3178.89 (7)C2—C3—C8—C7179.33 (8)
N1—C1—C2—C362.08 (9)C10—N2—C9—O17.33 (13)
C1—C2—C3—C4109.27 (9)N1—C1—C9—O128.32 (10)
C9—C1—C2—C3178.99 (6)C2—C1—C9—O192.29 (9)
C1—C2—C3—C871.22 (10)C2—C1—C9—N285.40 (8)
C8—C3—C4—C50.26 (15)C9—N2—C10—C1173.12 (9)
C2—C3—C4—C5179.77 (9)C11—C10—C12—O2121.60 (8)
C3—C4—C5—C60.61 (18)C11—C10—C12—O357.19 (9)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1···O50i0.888 (13)1.980 (13)2.7879 (9)150.5 (12)
N1—H2···O2ii0.914 (13)1.802 (13)2.7114 (9)172.5 (12)
N1—H3···O50iii0.910 (13)1.974 (12)2.8440 (9)159.3 (12)
N2—H4···O40iv0.825 (13)2.186 (13)2.9843 (9)163.0 (12)
C1—H11···O40iv1.000 (12)2.479 (12)3.2920 (10)138.1 (9)
O40—H401···O3v0.839 (19)1.933 (19)2.7679 (9)172.9 (17)
O40—H402···O2ii0.829 (17)2.462 (17)3.0030 (10)123.8 (14)
O40—H402···O10.829 (17)2.721 (17)3.4353 (11)145.3 (15)
O50—H501···O3v0.834 (15)1.850 (15)2.6818 (9)174.6 (14)
O50—H502···O10.834 (15)1.930 (15)2.7285 (8)160.0 (14)
Symmetry codes: (i) x1, y, z; (ii) x+1, y1/2, z+3/2; (iii) x1/2, y+1/2, z+2; (iv) x+1, y+1/2, z+3/2; (v) x+2, y1/2, z+3/2.

Experimental details

Crystal data
Chemical formulaC12H16N2O3·2H2O
Mr272.30
Crystal system, space groupOrthorhombic, P212121
Temperature (K)150
a, b, c (Å)7.6541 (2), 11.0918 (3), 17.5990 (5)
V3)1494.12 (7)
Z4
Radiation typeMo Kα
µ (mm1)0.09
Crystal size (mm)0.70 × 0.26 × 0.18
Data collection
DiffractometerSiemens SMART CCD
diffractometer
Absorption correctionEmpirical (using intensity measurements)
(SADABS; Sheldrick, 1996)
Tmin, Tmax0.936, 0.983
No. of measured, independent and
observed [I > 2σ(I)] reflections
19962, 6554, 5553
Rint0.021
(sin θ/λ)max1)0.806
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.035, 0.090, 1.02
No. of reflections6554
No. of parameters210
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.30, 0.16
Absolute structureFlack (1983)
Absolute structure parameter0.1 (5)

Computer programs: SMART (Bruker, 1998), SAINT (Bruker, 1998), SAINT, SHELXTL (Sheldrick, 1997), SHELXTL.

Selected geometric parameters (Å, º) top
O1—C91.2369 (9)N1—C11.4809 (10)
O2—C121.2515 (10)N2—C91.3284 (9)
O3—C121.2580 (10)
H401—O40—H402108.8 (16)H501—O50—H502101.2 (13)
N1—C1—C9—N2153.99 (7)N2—C10—C12—O3178.89 (7)
C1—C9—N2—C10170.21 (7)N1—C1—C2—C362.08 (9)
C9—N2—C10—C12164.26 (7)C1—C2—C3—C4109.27 (9)
N2—C10—C12—O22.32 (10)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1···O50i0.888 (13)1.980 (13)2.7879 (9)150.5 (12)
N1—H2···O2ii0.914 (13)1.802 (13)2.7114 (9)172.5 (12)
N1—H3···O50iii0.910 (13)1.974 (12)2.8440 (9)159.3 (12)
N2—H4···O40iv0.825 (13)2.186 (13)2.9843 (9)163.0 (12)
C1—H11···O40iv1.000 (12)2.479 (12)3.2920 (10)138.1 (9)
O40—H401···O3v0.839 (19)1.933 (19)2.7679 (9)172.9 (17)
O40—H402···O2ii0.829 (17)2.462 (17)3.0030 (10)123.8 (14)
O40—H402···O10.829 (17)2.721 (17)3.4353 (11)145.3 (15)
O50—H501···O3v0.834 (15)1.850 (15)2.6818 (9)174.6 (14)
O50—H502···O10.834 (15)1.930 (15)2.7285 (8)160.0 (14)
Symmetry codes: (i) x1, y, z; (ii) x+1, y1/2, z+3/2; (iii) x1/2, y+1/2, z+2; (iv) x+1, y+1/2, z+3/2; (v) x+2, y1/2, z+3/2.
 

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